This Program Project Grant application is directed at identifying small molecules that inhibit dual specificity phosphatases, such as Cdc25B;tubulin/microtubules;or motor proteins. JR oxime, an analogue of Curacin A directed at the colchicine binding site of tubulin was evaluated and found to be inactive. DA-3003-1, an irreversible phosphatase inhibitor was also evaluated and found to have marginal efficacy and a short halflife. JUN-1111, a dechlorinated analogue of DA-3003-1, is currently being investigated as is another phosphatase inhibitor, 5169131. Molecules such as dictyostatin 1, related to discodermolide, and directed against the paclitaxel binding site on tubulin, have been synthesized by Dr. Curran's group and should be available for in vivo testing within the first year. This Core is responsible for the preclinical evaluation of three, targeted, small molecules each year in rodents. Determination of the maximum tolerated doses of the compounds and efficacy in early xenograft models of prostate, colon, ovarian, and/or breast cancer will be determined first. If the compounds demonstrate activity or if they are the lead compound of a series of analogues of a particular structure, this evaluation will also include development of analytical methods for detection of the compounds in biological matrices and definition of plasma pharmacokinetics after i.v. and other routes of administration of the compounds at their maximum tolerated dose. The effects of the compounds on their molecular targets within the tumor xenografts will also be investigated in additional cohorts of animals included on the pharmacokinetic studies and the efficacy studies. The compounds selected for study in this Core will have been prioritized through the decision network of the Program Project Grant. The results of the studies conducted in this Core will provide information on the metabolism and pharmacokinetics of lead compounds that will be used by the Projects and the bioformatics Core in the modification of structures or the selection of new lead compounds. Data generated in this Core will provide the basis for the support of an IND to the FDA for the most promising lead compounds.
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